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Vol. 68, No. 2, 1998
Issue release date: August 1998
Neuroendocrinology 1998;68:77–88
(DOI:10.1159/000054353)

Exogenous Glutamate Enhances Glutamate Receptor Subunit Expression during Selective Neuronal Injury in the Ventral Arcuate Nucleus of Postnatal Mice

Hu L. · Fernstrom J.D. · Goldsmith P.C.
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Abstract

Administration of high doses of glutamate (Glu) leads to selective neurodegeneration in discrete brain regions near circumventriclular organs of the early postnatal mouse. The arcuate nucleus-median eminence complex (ARC-ME) appears to be the most Glu-sensitive of these brain regions, perhaps because of the intimate relationships between its neurons and specialized astroglial tanycytes. To investigate the mechanism of Glu-induced neuronal loss, we administered graded doses of the sodium salt of glutamate (MSG) to postnatal mice, measured their plasma Glu concentrations, and performed microscopic analyses of the ARC-ME region 5 h after treatment. Nursing, 7-day-old mouse pups (CD1, Charles River, Hollister, Calif.) were injected subcutaneously with single doses of 0.1–0.5 or 1.0–4.0 mg of MSG per g BW, or with water vehicle alone. Mice were decapitated 5 h later and the brains immediately fixed by immersion in buffered aldehydes. Frontal vibratome tissue sections at comparable levels of the ARC-ME were examined by light microscopy. A dose of 4.0 mg MSG/g BW caused neurodegeneration throughout the ARC region, while 1.0 mg/g MSG resulted in less extensive damage. Injection of 0.2 mg MSG/g BW, which raised plasma Glu concentrations 17-fold after 15 min, was the minimum dose tested at which nuclear and cytoplasmic changes were observed in a small group of subependymal neurons near the lateral recesses of the third ventricle. Higher doses of 0.3–0.5 mg MSG caused injury to additional neurons situated farther laterally, but damage remained confined to the ventral region of the ARC nucleus. Ultrastructural examination showed some subependymal neurons with pyknotic nuclei, reduced cytoplasmic volume, and swollen subcellular organelles, while others had fragmented and condensed nuclear material. Immunostaining for tyrosine hydroxylase indicated that dopamine neurons were spared at the threshold dose, but suffered damage after higher doses of MSG. Immunostaining for Glu receptor subtypes revealed that 0.2 mg MSG/g BW enhanced neuronal expression of NMDAR1 and of GluR2/4, and that higher doses of MSG preferentially increased NMDAR1 expression in injured neurons. These results extend previous reports of Glu sensitivity in the ARC-ME region of 7-day postnatal mice. A dose of 0.2 mg MSG/g BW s.c. causes clear but discrete injury to specific subependymal neurons of undetermined phenotype near the base of the third ventricle. Slightly higher doses of MSG evoke damage of additional neurons confined to the ventral region of the ARC traversed by tanycytes. These same greater amounts of MSG promote dose-related increase in the expression of NMDAR1 more than of GluR2/4 in injured ARC neurons, suggesting that elevated Glu receptor levels may contribute to or be related to neuronal cell death. Taken together with previous findings, the data suggest that Glu responsitivity in the ARC-ME of the postnatal mouse may result from transient developmental conditions involving the numerical ratios and juxtaposition between tanycytes and neurons, expression of Glu receptors, and perhaps other ontogenetic factors which may not persist in the mature adult.



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References

  1. Ankacrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P: Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995;15:961–973.
  2. Bonfoco E, Krainc D, Ankacrona M, Nicotera P, Lipton SA: Apoptosis and necrosis: Two distinct events induced respectively by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 1995;92:7162–7166.
  3. Brorson JR, Manzolillo PA, Miller RJ: Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells. J Neurosci 1994;14:187–197.

    External Resources

  4. Choi DW, Rothman SM: The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 1990;13:171–182.
  5. Weindl A, Joynt RJ: The circumventricular organs; in Knigge KM, Scott DE, Weindl A (eds): Brain-Endocrine Interaction. Median Eminence: Structure and Function. Int Symp, Munich, 1971. Basel, Karger, 1972, pp 280–297.
  6. Olney JW: Excitotoxic amino acids: Research applications and safety implications; in Filer LJ Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology, New York, Raven Press, 1979, pp 287–331.
  7. Heywood R, Worden AN: Glutamate toxicity in laboratory animals; in Filer LJ Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology. New York, Raven Press, 1979, pp 203–215.
  8. Reynolds WA, Butler V, Lemkey-Johnston N: Hypothalamic morphology following ingestion of aspartame or MSG in the neonatal rodent and primate: a preliminary report. J Toxicol Environ Health 1976;2:471–480.

    External Resources

  9. Holzwarth-McBride MA, Hurst EM, Knigge KM: Monosodium glutamate induced lesions of the arcuate nucleus. I. Endocrine deficiency and ultrastructure of the median eminence. Anat Rec 1976;186:185–205.

    External Resources

  10. Sved AF, Fernstrom JD: Effects of glutamate administration on pituitary function; in Filer LJ Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology. New York, Raven Press, 1979, pp 275–285.
  11. Attwell D, Barbour B, Szatkowski M: Nonvesicular release of neurotransmitter. Neuron 1993;11:401–407.

    External Resources

  12. Eurenius L, Jarskar R: Electron microscope studies on the development of the external zone of the mouse median eminence. Z Zellforsch Mikrosk Anat 1971;122:488–502.

    External Resources

  13. Kanai Y, Hediger MA: Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 1992;360:467–471.
  14. Levi G, Raiteri M: Carrier-mediated release of neurotransmitters. Trends Neurosci 1993;16:415–419.
  15. Pardridge WM: Regulation of amino acid availability to brain: Selective control mechanisms for glutamate; in Filer LJ Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology. New York, Raven Press, 1979, pp 125–137.
  16. Hu L, Goldsmith PC: Monosodium glutamate increases glutamate receptor expression coincident with loss of arcuate neurons in the postnatal mouse. 10th Int Congr Endocrinol, San Francisco 1996.
  17. Takasaki Y, Matsuzawa Y, Iwata S, O’hara Y, Yonetani S, Ichimura M: Toxological studies of monosodium L-glutamate in rodents: Relationships between routes of administration and neurotoxicity; in Filer LJ Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology. New York, Raven Press, 1979, pp 255–285.
  18. Takasaki Y: Studies on brain lesion by administration of monosodium L-glutamate to mice. I. Brain lesions in infant mice caused by administration of monosodium L-glutamate. Toxicology 1978;9:293–305.
  19. Goldsmith PC, Thind KK, Perera AD, Plant TM: Glutamate-immunoreactive neurons and their GnRH neuronal interactions in the monkey hypothalamus. Endocrinology 1994;134:858–868.
  20. Goldsmith PC, Thind KK: Morphological basis for neuronal control of GnRH secretion in the monkey. J Endocrinol 1995(suppl 2):1–14.
  21. Stegink LD, Reynolds AW, Filer LJJ, Baker GL, Daabees TT, Pitkin RM: Comparative metabolism of glutamate in the mouse, monkey, and man; in Filer LJ Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology. New York, Raven Press, 1979, pp 85–102.
  22. Bizzi A, Veneroni E, Salmona M, Garattini S: Kinetics of monosodium glutamate in relation to its neurotoxicity. Toxicol Lett 1977;1:123–130.

    External Resources

  23. O’Hara Y, Iwata S, Ichimure M, Sasaoka M: Effect of administration routes of monosodium glutamate on plasma glutamate levels in infant, weanling and adult mice. J Toxicol Sci 1977;2:281–290.
  24. Stegink LD, Shepherd JA, Brummel MC, Murray LM: Toxicity of protein hydrolysate solutions: Correlation of glutamate dose and neuronal necrosis to plasma amino acid levels in young mice. Toxicology 1974;2:285–299.
  25. Airoldi L, Bizzi A, Salamona M, Garattini S: Attempts to establish the safety margin for neurotoxicity of monosodium glutamate; in Filer LR Jr, Garattini S, Kare MR, Reynolds AW (eds): Glutamic Acid: Advances in Biochemistry and Physiology. New York, Raven Press, 1979, pp 321–331.
  26. Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A: Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 1997;17:5046–5061.
  27. Dessi F, Charriaut-Marlangue C, Khrestchatisky M, Ben-Ari Y: Glutamate-induced neuronal death is not programmed cell death in cerebellar culture. J Neurochem 1993;60:1953–1955.
  28. Kure S, Tominaga T, Yoshimoto T, Tada K, Narisawa K: Glutamate triggers internucleosomal DNA cleavage in neuronal cells. Biochem Biophys Res Commun 1991;179:39–45.
  29. Hartley Z, Dubinksky JM: Changes in intracellular pH associated with glutamate excitoxicity. J Neurosci 1993;13:4690–4699.
  30. Levi G, Patrizio M: Astrocyte heterogeneity: endogenous amino acid levels and release evoked by non-N-methyl-D-aspartate receptor agonists and by potassium-induced swelling in type-1 and type-2 astrocytes. J Neurochem 1992;58:1943–1952.

    External Resources

  31. Seeburg PH: The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci 1993;16:359–365.
  32. Smirnova T, Laroche S, Errington ML, Hicks AA, Bliss TV, Mallet J: Transsynaptic expression of a presynaptic glutamate receptor during hippocampal long-term potentiation. Science 1993;262:433–436.

    External Resources

  33. McDonald JW, Fix AS, Tizzano JP, Schoepp DD: Seizures and brain injury in neonatal rats induced by 1S,3R-ACPD, a metabotropic glutamate receptor agonist. J Neurosci 1993;13:4445–4455.
  34. de Vitry F, Picart R, Jacque C, Tixier-Vidal A: Glial fibrillary acidic protein: A cellular marker of tanycytes in the mouse hypothalamus. Dev Neurosci 1981;4:457–460.

    External Resources

  35. Levitt P, Rakic P: Immunoperoxidase localization of glial fibrillary acidic protein in radial glial cells and astrocytes of the developing rhesus monkey brain. J Comp Neurol 1980;193:815–840.
  36. Abraham R, Swart J, Golberg L, Coulston F: Electron microscopic observations of hypothalami in neonatal rhesus monkeys (Macaca mulatta) after administration of monosodium-L-glutamate. Exp Mol Pathol 1975;23:203–213.

    External Resources

  37. Roessman U, Valasco ME, Sindley SD, Gambetti P: Glial fibrillary acidic protein (GFAP) in ependymal cells during development. An immunocytochemical study. Brain Res 1980;200:13–21.
  38. Lehmann A, Jonsson T: MK-801 selectively protects mouse arcuate neurons in vivo against glutamate toxicity. Neuroreport 1992;3:421–424.

    External Resources

  39. Petralia RS, Wenthold RJ: Light and electron immunocytochemical localization of AMPA-selective glutamate receptors in the rat brain. J Comp Neurol 1992;318:329–354.

    External Resources

  40. Price MT, Olney JW, Lowry OH, Buchsbaum S: Uptake of exogenous glutamate and aspartate by circumventricular organs but not other regions of brain. J Neurochem 1981;36:1774–1780.

    External Resources

  41. Madl JE, Burgesser K: Adenosine triphosphate depletion reverses sodium-dependent, neuronal uptake of glutamate in rat hippocampal slices. J Neurosci 1993;13:4429–4444.


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